Cancer is well known to be associated with alterations in
membrane protein glycosylation (Bird, N. C., Mangnall, D., and Majeed, A. W. (2006) Biology of colorectal liver
metastases: A review. J. Surg. Oncol. 94, 68-80; Dimitroff, C. J., Pera, P., Dall'Olio, F., Matta, K. L., Chandrasekaran, E. V., Lau, J. T., and Bernacki, R. J. (1999) Cell surface
n-acetylneuraminic acid alpha2,3-galactoside-dependent intercellular adhesion of human
colon cancer cells. Biochem. Biophys. Res. Commun. 256, 631-636; and Arcinas, A., Yen, T. Y., Kebebew, E., and Macher, B. A. (2009) Cell surface and secreted
protein profiles of human
thyroid cancer cell lines reveal distinct
glycoprotein patterns. J.
Proteome Res. 8, 3958-3968). Equally, it has been well established that
tumor-associated
inflammation through the release of pro-inflammatory
cytokines is a common cause of reduced hepatic
drug metabolism and increased toxicity in advanced
cancer patients being treated with cytotoxic
chemotherapies. However, little is known about the impact of bearing a
tumor (and downstream effects like
inflammation) on liver
membrane protein glycosylation. In this study, proteomic and glycomic analyses were used in combination to determine whether liver
membrane protein glycosylation was affected in mice bearing the
Engelbreth-Holm Swarm sarcoma.
Peptide IPG-IEF and label-free quantitation determined that many
enzymes involved in the protein glycosylation pathway specifically;
mannosidases (Man1a-I, Man1b-I and Man2a-I),
mannoside N-acetylglucosaminyltransferases (Mgat-I and Mgat-II),
galactosyltransferases (B3GalT-VII, B4GalT-I, B4GalT-III, C1GalT-I, C1GalT-II, and GalNT-I), and
sialyltransferases (ST3Gal-I, ST6Gal-I, and ST6GalNAc-VI) were up-regulated in all livers of
tumor-bearing mice (n = 3) compared with nontumor bearing controls (n = 3). In addition, many cell surface
lectins: Sialoadhesin-1 (Siglec-1),
C-type lectin family 4f (
Kupffer cell receptor), and
Galactose-binding lectin 9 (Galectin-9) were determined to be up-regulated in the liver of
tumor-bearing compared with control mice. Global
glycan analysis identified seven N-
glycans and two O-
glycans that had changed on the liver
membrane proteins derived from
tumor-bearing mice. Interestingly, α (2,3)
sialic acid was found to be up-regulated on the liver membrane of
tumor-bearing mice, which reflected the increased expression of its associated
sialyltransferase and
lectin receptor (siglec-1). The overall increased sialylation on the liver membrane of Engelbreth-Holm Swarm bearing mice correlates with the increased expression of their associated
glycosyltransferases and suggests that glycosylation of
proteins in the liver plays a role in
tumor-induced liver
inflammation.